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Chapter 1: Introduction: Cell Cycle Regulation via TPX2 Inhibition in Cancer
1.1 Introduction
“Cancer" encompasses a collection of disorders that arise from genetic abnormalities, resulting in the disruption of cellular processes and giving rise to uncontrolled proliferation, metastasis, and notably, angiogenesis. The formation of neoplasms is contingent upon the presence and activity of proto-oncogenes, tumour suppressor genes, and DNA repair genes. Mutations in key genes such as p53 and BRCA1/2 have been identified as factors that heighten cancer susceptibility. The development of many forms of cancer may be attributed to mutations, epigenetic alterations, and chromosomal abnormalities. Examples of frequent malignancies include leukaemia affecting blood tissues, sarcoma affecting bones and soft tissues, and carcinoma affecting organ linings. The area of anti-cancer therapy, which is being significantly influenced by genetic research, focuses on identifying shared disease markers for targeted treatments and forecasting patient outcomes. In this study, a comprehensive discussion about the effectiveness of the mitotic kinase Aurora A and its regulator TPX-2 regarding viable drug targets for the treatment of cancer was conducted. The aim, objectives, questions under investigation, a complete framework of the research, and background of the protein target under investigation are some of the important aspects of this chapter.
1.2 Background
Cancer is a group of diseases distinguished by aberrant and unregulated cellular expansion, primarily attributed to genetic abnormalities that disrupt the normal cellular signalling mechanisms governing cell division and apoptosis. This results in the unrestrained expansion of these malignant cells, causing "metastasis" and "angiogenesis.". These genetic alterations, commonly referred to as drivers due to their capacity to initiate tumour formation, provide “somatic cells” within a specific tissue with a competitive edge over adjacent cells. The main set of genes whose “genetic alteration” is seen to play a significant role in tumour initiation includes “proto-oncogenes, tumour-suppressor genes,” and “DNA-repair genes.". “Neoplasms” arise due to the accumulation of transmitted and somatic genetic alterations within these sets of genes. The most typical example of this kind of change in these sets of genes involves mutations in "tumour suppressor genes" like p53, as well as "DNA repair genes" like the "BRCA1 and BRCA2 genes." Individuals who possess a hereditary mutation in any of the aforementioned genes are at an elevated susceptibility to certain forms of cancer, including breast and ovarian cancer.
Common Types
“Mutation, epigenetic alterations," and “chromosomal alterations” lead to more than fifty various types of cancer, where the most common type includes carcinoma, or cancer affecting the epithelial lining of different organs like the lungs, pancreas, and skin. Apart from carcinoma, the other common types include “sarcoma and leukaemia," where sarcoma refers to cancer growth of bones and soft tissues, while leukaemia refers to the malignant growth within the blood tissues of bone. The most common example is “Hodgkin lymphoma,” which originates in the B-cells of bone marrow. Due to the development of genetics, a primary objective in the field of investigation into cancer has involved the identification of cancer promoter genes or targets that apply to many types of tumours. The discovery of these indicators has contributed to the emergence of the tailored anti-cancer therapy paradigm and, in a broader context, has spurred the exploration of genetic markers that might predict prognosis and treatment response.
Within the network of co-functionality, the specific gene of “TPX2” was identified, which was crucial for the survival of cancer cells. The inactivation of the BRCA2 gene induced a mechanism that reduced the possibility of survival of those cancer cells that are genetically unstable. It was also being investigated about the importance of the “TPX2 protein" and whether the reduction of the amount of this protein and its associated kinase Aurora A would also reduce the cancer cell viability (Biswas et al. 2020). But those cells should be deficient of “BRCA2 protein.". Several investigations are being carried out by the researchers on the mouse model that showed those cells with a depleted BRCA2 gene and protein had increased sensitivity towards the inhibitor cell cycle “Aurora-A Kinase” (Gavriilidisa et al. 2015). These aurorae are of three types: A, B and C. This shows that drugs targeting the regulatory protein “TPX2 protein” and the mitotic “kinase Aurora A” would help in the reduction of the growth of cancer cells in the body. This should be studied properly.
1.3 Research aim
The research aims to investigate and understand the critical role of Auroras and their associated signalling proteins in the prevention of diseases. Also, to understand the small kinase inhibitors of protein inhibitors. The study also aims to investigate the efficacy of these molecules in vitro and in vivo in the prevention of diseases.
1.4 Research Objectives
The objectives of the study are given below.
- To investigate the efficiency of the TPX2 regulator in arresting the growth of cancer cells in different cancer subtypes.
- To investigate the mechanism of cell cycle inhibition by the TPX2 regulator as a result of suppression of auroras by the drugs.
- To analyse the in vitro and in vivo condition functionality of the drugs.
- To understand the mechanism of cell cycle regulation.
- To understand the mechanism of the drugs in the stages of the cell cycle.
1.5 Research Questions
The questions that were being investigated are given below.
- What is the efficiency of the TPX2 regulator in arresting the growth of cancer cells in different cancer subtypes?
- How does the mechanism of the inhibition of the cell cycle by the TPX2 regulator happen as a result of the suppression of auroras by the drugs?
- How do the drugs target the TPX2 regulator functions in in vitro and in vivo conditions?
- What are the mechanisms of the cell cycle regulation?
- What is the mechanism of the TPX2 regulatory drugs in cell cycle stages?
1.6 Research Rationale
The rationale behind the conduct of the research is to understand the mechanism of the TPX2 regulators in the inhibition of the cell cycle. As per this technology, the principal mechanism of inhibition of the growth of the cancer cells is through the use of TPX2 inhibitors. As a result, Aurora kinase A would also be restricted. This would improve the possibility of reducing cancer cell growth (Bavetsias 1, et al. 2015). The improvement of the cell cycle regulation for the cancer cells would prevent the cancer spread. Although this technology is new and needs more investigation,.
1.7 Research Significance
Mitotic kinase Aurora A was activated by a phosphorylation mechanism and “TPX2 protein.". TPX2 is a microtubule-associated protein. The targeting of this aurora A protein by the TPX2 inhibitory drugs leads to the arrest of the cell cycle that was upregulated in cancer cells. This would help in the prevention of the progression of cancer and tumour cell lines (Galetta et al. 2020). However, this mechanism of cell cycle arrest through the use of drugs and stopping the growth of the cancer cells is still new and should be investigated more. This study would help to find solutions regarding the use of this technology in preventing the spread of cancer (Bamodu et al., 2021). And this would help to improve the possibility of cancer drug design and development.
1.8 Research Framework
The framework of the research is given below.
![Research Framework]( "Research Framework")
Figure 1: Research Framework
Conclusion
In conclusion, it could be said that the aurora kinase plays a big role in the regulatory mechanism of the cell cycle. The aurora kinase inhibitors are important in the regulation of the cell cycle, which is itself regulated by the use of the TPX2 inhibitors. Using this principle mechanism, researchers tried to develop and test drugs that would control the growth of cancer cells. However, this developmental mechanism of preventive cancer drugs needs more investigation and clinical trials. This section discusses the aim, objective, questions to be investigated, and also the rationale behind the research, as well as the significance of the research study. The overall framework of the study was discussed as well.
References
Journals
Aurora Kinase inhibitors: Current Status and Outlook
Vassilios Bavetsias1 and Spiros Linardopoulos Frontiers in Oncology Front. Oncol. 2015:5:278.
Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review. Paschalis Gavriilidisa, c, Alexandros Giakoustidisb, Dimitrios Giakoustidisb. J Clin Med Res. 2015;7(10):742-751.
Bamodu, O.A., Tzou, K.Y., Lin, C.D., Hu, S.W., Wang, Y.H., Wu, W.L., Chen, K.C. and Wu, C.C., 2021. Differential but concerted expression of HSD17B2, HSD17B3, SHBG and SRD5A1 testosterone tetrad modulate therapy response and susceptibility to disease relapse in patients with prostate cancer. Cancers, 13(14), p.3478.
Biswas, K., Sarkar, S., Said, N., Brautigan, D.L. and Larner, J.M., 2020. Aurora B kinase promotes CHIP-dependent degradation of HIF1α in prostate cancer cells. Molecular cancer therapeutics, 19(4), pp.1008-1017.
Galetta, D. and Cortes-Dericks, L., 2020. Promising therapy in lung cancer: spotlight on aurora kinases. Cancers, 12(11), p.3371.
van Gijn, S.E., Wierenga, E., van den Tempel, N., Kok, Y.P., Heijink, A.M., Spierings, D.C., Foijer, F., van Vugt, M.A. and Fehrmann, R.S., 2019. TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells. Oncogene, 38(6), pp.852-867.
